reduced EF heart failure & preserved EF heart failure

1. PATHOPHYSIOLOGICAL BASIS OF
HEMODYNAMICS OF LOW OUTPUT HEART
FAILURE
Aniruddha Mandal
Chair person
Dr. Dipankar Ghosh
Dastidar

2.  Heart failure (HF) is a clinical syndrome that
occurs in patients who, because of an
inherited or acquired abnormality of cardiac
structure and/or function, develop a
constellation of clinical symptoms (dyspnea
and fatigue) and signs (edema and rales) that
lead to frequent hospitalizations, a poor
quality of life, and a shortened life expectancy
DEFINITION

3.  CARDIAC OUTPUT ( C O.): Quantity of blood
pumped into the aorta each minute by the
heart
STROKE VOLUME × HEART RATE
 DEPENDS DIRECTLY ON :
(1) body metabolism
(2) exercise
(3) age
(4) Body surface area.
 CARDIAC INDEX : C O. / BODY SURFACE AREA

4.  Cardiac Output =
Arterial Pressure / Total
Peripheral Resistance
 Normally resistence is sum of
Blood Flow Regulation in All the
Local Tissues
 Two primary factors in cardiac
output regulation:
(1)cardiac pumping capacity
(2)venous return

5. CARDIAC FACTOR CONTROL OF
CARDIAC OUTPUT
HYPOEFFECTIVE HEART
Myocardial ischemia & infarction
 Myocarditis
 Cardiac metabolic derangement
 Cardiac tamponade
Arrythmia
Severe valvular heart disease
Congenital heart disease

6.  DETERMINANT OF VENOUS
RETURN
 Mean systemic filling
pressure (psf) --Degree of
filling of the systemic
circulation
 Right atrial pressure----
backward force
 Resistance to blood flow
VENOUS RETURN – DETERMINATION
OF CO.

7. INCREASED IN
 ↑ BLOOD VOLUME
 ↑ SYMPATHETIC
ACTIVITY DUE TO
CONSTRICTION OF
 Capacitance vessels
 Pulomonary vessels
 Heart chambers
 arteriole
MEAN SYSTEMIC FILLING
PRESSSURE

8. VENOUS RETURN = CARDIAC OUTPUT

9. NERVOUS & REFLEX CONTROL OF
OUTPUT

10. Sympathetic stimulation→effect 0n
heart
↑Na+ ,H2O
absorption-
kidney
↓ renal
blood
flow
↑AVP,RAS
↑ 𝑝𝑠𝑓.
Immediate activation of REFLEXEES
Baro Chemo
Brain
ischemia
Heart
damage
Heart suddenly severely damaged
↓ CO.
Damming of blood in
vein
Spectrum of acute heart failure

11. Reflex get blunted in 2-3 days.
SEMICHRONIC STAGE ensues→
Kidney
fluid
retention
↑ psf
Distended
vein→
↓ venous
resistence
Progressive recovery of
heart
Reperfusin, compensatory
hypertrophy,collateral,

12. Acute heart
failure
compensated
With
Sympathetic
support
After someday
symp. Support
not needed
Decompensated
Massive myocyte loss,
Overstretching,
Heart muscle edema,
PROGRESSION

13.  CARDIORENAL MODEL- excessive salt and water
retention caused by abnormalities of renal blood flow
 CARDIOCIRCULATORY OR HEMODYNAMIC MODEL-
abnormal pumping capacity of the heart
- not adequately explain relentleess progress
 PROGRESSIVE MODEL - primary determinant
 neurohumoral activation
 left ventricular remodeling
CHRONIC HEART FAILURE AS A
PROGRESSIVEMODEL

15. Activation of the Sympathetic (Adrenergic)
Nervous System
 Increased circulating Norepinephrine (NE)-2-3 times
 Heart extracts NE from the arterial blood & also
synthesized in myocardium.
 With progression cardiac depletion of NE-“exhaustion”
phenomenon
↓ myocardial tyrosine hydrxylase
 ↓ NE uptake
NEUROHUMORAL MECHANISM

17. β- adrenergic desensitization

18.  Activated comparatively later by
1. Renal hypoperfusion
2. ↓ Na delivery to macula densa
3. Sympathetic stimulation
 Angiotensin receptor- G protein coupled -2 types
 AT1 –vasoconstriction, cell growth, aldosterone and
catecholamine release-
 AT2 –vasodilation, inhibition of cell growth, natriuresis,
and bradykinin release-
Activation of the Renin-Angiotensin System

19. s

20. ANGIOTENSIN ĪĪ- short term circulatory support.
 ↑ Na+, water, absorption, thirst, AVP , aldosteron
 ↑ NE secretion
 induce fibrosis
ALDOSTERONE
 Effects on MYOCARDIUM & VASCULATURE causing
fibrosis & hypertrophy → ↓ 𝑐𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 & ↑ 𝑠𝑡𝑖𝑓𝑓𝑛𝑒𝑠𝑠
 Endothelial dysfunction
 Baroreceptor dysfunction
 ↓NE uptake
 Oxidative stress → inflammation in target tissue
Cont.. RAAS

21.  REACTIVE O2 SPECIES (ROS) ACTIVITY ↑ due to :
 Mechanical strain
 Neurohormone
 Inflammatory cytokine
 ↓ NOS activity
 EFFECT :
 Hypertrophy
 Reexpression of fetal gene programme
 Fibroblast proliferration→↑ collagen, MMP
 ↓ bioavailability of NO in peripheral vasculature
OXIDATIVE STRESS(ROS)

22. Neurohormonal Alterations of Renal
Function

23.  VASODILATTORY PROSTAGLANDIN: PGE2, PGI2
 NO, bradykinin, adrenomedullin, apelin
 NATRIURETIC PEPTIDES : ANP, BNP, CNP, DNP,
urodilantin
 Renal effects become blunted with advancing HF
COUNTER REGULATORY NEUROHORMONE

24.  ANP secreted in short burst in ACUTE changes
 BNP regulated transcriptionally as CHRONIC response
 PROHORMON cleaved to
 large biologically inactive N-terminal fragments (NT-ANP or NT-
BNP)
 smaller biologically active peptides (ANP or BNP)
 degraded by neutral endopeptidase
 Degraded by NEUTRAL ENDOPEPTIDASE & VASOPEPTIDASE
 Candoxatrilat endopeptidase inhibitor
 Omapatrilat inhibits both neutral endopeptidase and ACE
NATRIURETIC PEPTIDES

25. Neurohormonal Alterations in the
PERIPHERAL VASCULATURE

26. Secretion enhanced by
 Vasoactive agent (NE, angiotensin, thrombin)
 Cytokines
EFFECT
 Vasoconstriction
 cell proliferation
 pathologic hypertrophy
 Fibrosis
 Increased contractility
 ↑ Pulmonary artery pressure, resistence
ENDOTHELIN

27.  NEUROPEPTIDE Y released together with NE &
inhibit NE secretion--- blunted in HF
 UROTENSIN İİ :
 most potent endogenous cardiostimulatory
peptide identified thus far
 Trophic & mitogenic to vascular smooth muscle,
myocyte, fibroblast
 Bradykinin, Aplein, Adrenomedullin- offseting
vasoconstriction, antidiuresis, hypertrophy

28. Disrupted subcellular location
of NOS
 ↓ NOS3 in HF
 Nitroso redox imbalance–
unopposed activity of
xanthin oxidase (↓NOS1)
 Remodeling ↓ in NOS2
deficiency
NITRIC OXIDE

29.  TNF, PAI-1, TGF-β, resistin
and-
 Leptin : hypertension,
hypertrophy, ↑ in HF of
obese patient
 ADIPONECTIN ↓ infarct
size, apoptosis
it ↓ in hear failure
ADIPOKINES

30. INFLAMMATORY( IL-6, TNF) &
ANTIINFLAMMATORY(IL-10) IMBALANCE

31.  Traditionally described in
anatomical term
 BUT there is also
alteration in
A. Biology of cardiac
myocyte
B. Volume of myocyte &
nonmyocyte
component
C. Geometry &
architecture of
ventricular chamber
LEFT VENTRICULAR REMODELING

33. Alterations in the BIOLOGY
CARDIAC MYOCYTE HYPERTROPHY

34. Alterations in Excitation-Contraction
Coupling

35. ↓ SERCA2
↓phospholamban
phosphorylation;
Leakage of
Ryanodine
receptor(hyperphs
phorylation)
phosphorylation&
dysfunction of L –
type Ca++ cnl.
Ca++ entry in
reverse mode by
Na+/Ca++
exchanger.
Slower delivery
of ca++ to
contractile
apparatus &
slow fall in
diastole;
change in
abundance/
phosphorylation
in regulatory
protein
Abnormal
prolongation
of A.P.
↓ force of
CONTRACTION
&
RELAXATION
Cont..

36.  Shift to fetal gene program – fetal isoform of myosin
heavy chain(MHC; α →β)
 ↓ Myofibrilar ATPase & Myosin ATPase
 Myocytolysis – proteolysis of myofilament
 Alteration in myofilament regulatory protein
 Altered activity of Myosin light chain ; troponin
tropomyosin complex
 CYTOSKELETAL PROTEIN (actin, desmin, dystrophin,
vinculin) altered expression
Abnormalities in Contractile and
Regulatory Proteins

37.  NECROSIS :
 Directly from ischemia, myocardial injury, toxin, infection
 From Neuroheumoral activation
 APOPTOSIS : induced by
 catecholamines acting through beta1-adrenergic receptor
 angiotensin II
 ROS, NO, inflammatory cytokines
 mechanical strain
 AUTOPHAGY:sequestering organelles and proteins in
a double-membrane vesicle inside the cell
(autophagosome) → subsequently delivered to the
lysosome for degradation
Alterations in the Myocardium in
Heart Failure

38.  Type I and type III collagen ensures
 Structural integrity of adjoining myocytes
 Interaction of collagen and integrins with the
cytoskeletal proteins --maintainin alignment of
myofibrils
 Phenotypic conversion to myofibroblast
 ↑ collagen synthesis & ↑ MMP → ↑ Turnover
 Replacement fibrosis
FIBROBLAST

39. Alterations in the Left Ventricular
Structure & Geometry in Heart Failure

42. EXTERNAL PRESSURE & CO.

43. HEART
FAILURE
WITH
PRESERVED
EJECTION
FRACTION

45. Thank you